
Heightened self-reactivity of CD8+ T cells during thymic positive selection, as indicated by increased CD5 expression, predisposes them to an effector/memory-like phenotype and enhanced diabetogenic potential in non-obese diabetic (NOD) mice.


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Our understanding of autoimmune diabetes underscores the critical involvement of CD8+ T cells recognizing islet-specific antigens. However, the influence of thymic positive selection on diabetogenic CD8+ T cell development remains unclear. Using CD5 marker representing T-cell receptor (TCR) signal strength, we illustrated that naïve CD5hiCD8+ T cells of non-obese diabetic (NOD) mice with enhanced TCR signals displayed predisposed differentiated/memory T cell traits with increased activation and proliferation upon TCR stimulation, compared to CD5lo counterparts. Additionally, CD5hiCD8+ T cells exhibited gene expression landscape similar to effector T cells and exacerbated disease in transfer model. Interestingly, the protective effects of transgenic phosphatase Pep expression, which lowers TCR signaling and diabetes incidence, were abolished in NOD strain 8.3 with high CD5 expression linked to increased thymic positive selection. Strikingly, TCR repertoire analysis identified higher frequencies of autoimmune disease-related clonotypes in naïve CD5hiCD8+ cells, supporting that distinct effector functions arise from intrinsic TCR repertoire differences. Overall, CD5hiCD8+ clones may be potential targets for autoimmune diabetes treatment.

### Competing Interest Statement

The authors have declared no competing interest.

*   dLPC/NOD
    :   Lck distal promoter– Ptpn22 C line in NOD background
    dLPE/NOD
    :   Lck distal promoter– Ptpn22 E line in NOD background
    NOD
    :   non-obese diabetic

Thymic self-recognition-mediated TCR signal strength modulates antigen-specific CD8+ T cell pathogenicity in non-obese diabetic mice

distinct-thymic-self-recognition-shapes-the-pathogenicity-of-autoantigen-specific-cd8-t-cells-in-non-obese-diabetic-mice


Distinct Thymic Self-Recognition Shapes the Pathogenicity of Autoantigen-Specific CD8+ T Cells in Non-Obese Diabetic Mice
